Aberrant DNA strand break repair can result in mutations that include loss of heterozygosity, chromosomal rearrangements, and point mutations. The genomic instability that results from aberrant repair of double- strand breaks is known to be associated with cancer. The broad, long-term objective of the proposed research is to identify and characterize the role of DNA polymerase beta in the repair of strand breaks, and to further our understanding of the impact of aberrant repair on genomic instability. We have recently constructed a mouse that is conditionally deleted of the DNA polymerase beta gene, and provide evidence that this gene is involved in break repair. The specific aims of the grant are to test the hypothesis that Pol Beta, and specifically its DNA synthesis function, is critical for double strand break repair, and to test the hypothesis that tissues deleted of Pol Beta have higher frequencies of mutagenesis, and contain the types of mutations that are consistent with aberrant double strand break repair. To carry out our aims we will characterize double-strand break repair in mouse tissues that are conditionally deleted of the Pol Beta gene, and will obtain mutation frequencies and spectra, using three different transgenes that will be incorporated into the mice. These experiments have the potential to further our understanding of the relationship between genomic instability and the onset or progression of cancer.